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Previously, we reported that <i>Sargassum horneri (Turner) C. Agardh</i> (<i>S. horneri</i>) is a brown algae species that exerts anti-inflammatory activity toward murine macrophages. However, the anti-neuroinflammatory effects and the mechanism of <i>S. horneri</i> on microglia cells are still unknown. We investigated the anti-neuroinflammatory effects of <i>S. horneri</i> extract on microglia in vitro and in vivo. In the present study, we found that <i>S. horneri</i> was not cytotoxic to BV-2 microglia cells and it significantly decreased lipopolysaccharide (LPS)-induced NO production. Moreover, <i>S. horneri</i> also diminished the protein expression of iNOS, COX-2, and cytokine production, including IL-1β, TNF-α, and IL-6, on LPS-stimulated microglia activation. <i>S. horneri</i> elicited anti-neuroinflammatory effects by inhibiting phosphorylation of p38 MAPK and NF-κB. In addition, <i>S. horneri</i> inhibited astrocytes and microglia activation in LPS-challenged mice brain. Therefore, these results suggested that <i>S. horneri</i> exerted anti-neuroinflammatory effects on LPS-stimulated microglia cell activation by inhibiting neuroinflammatory factors and NF-κB signaling.